The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer

Nour Ghaddar, Shuo Wang, Bethany Woodvine, Jothilatha Krishnamoorthy, Vincent Hoef, Cedric Darini, Urszula Kazimierczak, Nicolas Ah-son, Helmuth Popper, Myriam Johnson, Leah Officer, Ana Teodósio, Massimo Broggini, Koren K. Mann, Maria Hatzoglou, Ivan Topisirovic, Ola Larsson, John Quesne () and Antonis E. Koromilas ()
Additional contact information
Nour Ghaddar: Sir Mortimer B. Davis-Jewish General Hospital
Shuo Wang: Sir Mortimer B. Davis-Jewish General Hospital
Bethany Woodvine: University of Leicester
Jothilatha Krishnamoorthy: Sir Mortimer B. Davis-Jewish General Hospital
Vincent Hoef: Karolinska Institute
Cedric Darini: Sir Mortimer B. Davis-Jewish General Hospital
Urszula Kazimierczak: Sir Mortimer B. Davis-Jewish General Hospital
Nicolas Ah-son: Sir Mortimer B. Davis-Jewish General Hospital
Helmuth Popper: Medical University of Graz
Myriam Johnson: Sir Mortimer B. Davis-Jewish General Hospital
Leah Officer: University of Cambridge
Ana Teodósio: University of Cambridge
Massimo Broggini: Laboratory of Molecular Pharmacology IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri”
Koren K. Mann: Sir Mortimer B. Davis-Jewish General Hospital
Maria Hatzoglou: Case Western Reserve University
Ivan Topisirovic: Sir Mortimer B. Davis-Jewish General Hospital
Ola Larsson: Karolinska Institute
John Quesne: University of Leicester
Antonis E. Koromilas: Sir Mortimer B. Davis-Jewish General Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.

Date: 2021
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DOI: 10.1038/s41467-021-24661-0

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